The linear-no threshold dose model has been used by governmental bodies as a policy matter to add-in many factors of safety from what is truly supported by science. This memo lays out the foundation from science & medicine publications that bear on the issue of whether or not the “single-fiber” or the “zero-no-threshold/linear-dose-response” theories are sufficiently grounded in science to form the basis of an expert opinion that would withstand a Daubert/Frye challenge. There are several different approaches presented.

The first approach is experimentally based and primarily focuses on recent work by Bernstein and colleagues, NIOSH and Wagner involving the administration of sanded joint compound containing “enriched Grade 7 chrysotile”.1 We’ve included a list of the publications with annotated take-away messages.

Second, we’ve included scientific articles explaining the assumptions upon which the zero-no-threshold/linear-dose-response model is based and papers demonstrating why it is not appropriate for evaluation of risks from chrysotile exposure.

Third we have included a couple of papers criticizing the use of the model to characterize risk from ionizing radiation because the same criticisms are valid with respect to use of the model to evaluate chrysotile risk.

Finally, we have included a couple of law journal-type papers that document the judicial trend toward rejecting that expert testimony purporting to demonstrate that every exposure significantly increases the risk of disease which is the foundation upon which the zero-no-threshold/linear-dose-response model is based.

Bernstein and Hoskins in “The Health Effects of Chrysotile: Current Perspective Based Upon Recent Data” (Regulatory Toxicology and Pharmacology, 2006 Aug:45(3):252-64 Epub 2006 Jul 11) state “[l]ow exposures to pure chrysotile do not present a detectable risk to health.”

The Bernstein, et al, study in “The Pathological Response and Fate in the Lung and Pleura of Chrysotile in Combination with Fine Particles Compared to Amosite Asbestos Following Short-Term Inhalation Exposure: Interim Results” (Inhalation Toxicology 2010, 1-26) documents the extraordinary difference in pleural response to inhaled amosite and sanded joint compound containing enriched chrysotile. (“Enriched” means the mixture was seeded with sufficient long chrysotile fibers to meet the animal testing guidelines of the European Commission which requires a certain number of carcinogenic length fibers, i.e. >20 microns in length.) The fact that inhaled joint compound resulted in no pathological response in rat pleura following inhalation supports the proposition that there is a threshold for pathogenicity, at least with respect to chrysotile.

“Quantification of the Pathological Response and Fate in the Lung and Pleura of Chrysotile in Combination with Fine Particles Compared to Amosite-Asbestos Following Short-Term Inhalation Exposure” (Inhalation Toxicology, 2011 June:23(7):372-91) by Bernstein, et al, is a follow-up to the previous paper which confirms the absence of pathological response in the pleura on inhalation of sanded joint compound containing chrysotile. This is compared to a very robust response in the pleura to inhaled amosite.)

Platek, et al, in “Chronic Inhalation of Short Fiber Asbestos” (Fundamental and Applied Toxicology, 5: 327-340 (1985)), report no pathological response in rat lungs following exposure to 1 f/cc for 1.5 years, 7 hours/day, 5 days/week, despite mean retained lung burdens of 294 million f/g dry tissue of which 23 million were longer that 5 microns.

Wagner in “The Comparative Effects of Three Chrysotiles by Injection and Inhalation in Rats,” (IARC Pub #30; Biologic Effects of Mineral Fibres, 30(1): 363-72 (1980)) reports on an 18-month inhalation study with Grade 7 chrysotile 5 days/week, 7 hours/day with no mesotheliomas detected at a concentration of 1040 f/cc.

While these studies suffer from the classic “you can’t prove the negative” logical flaw, they still offer compelling evidence that there are levels of chrysotile exposure that result in no pathological response at all. That lack of response is completely opposite to the very robust pathological response Bernstein observed with short-term amosite exposure in both lung and pleura.

This group of studies/papers discusses the fact that the no-threshold/linear-dose response model is based on assumptions and the precautionary principle, not scientific study. Indeed, it is clear that the risk from low-dose exposures is so small, particularly with respect to chrysotile, that it cannot be determined by epidemiological study.

Peto and Doll, Asbestos, Effects on Health of Exposure to Asbestos (1986 U.K. Health and Safety Commission) state at page 32:

For both lung cancer and mesothelioma there is clear, qualitative evidence that excess mortality is increased by more intense exposure, but available data are not sufficiently detailed to establish the form of dose dependence. We shall assume for both diseases that the increase in risk is directly proportional to intensity (dust level) for an exposure of fixed duration at a given age. This is consistent with available data . . . but there are examples of both upward and downward curvature in dose response for other carcinogens, and the assumption of dose linearity, although scientifically plausible, is not demonstrably correct. Nor is it demonstrable that there is no threshold below which cancer is not produced. . . . No threshold for the carcinogenic effect of asbestos has been demonstrated in humans or in laboratory animals and in the absence of positive evidence of a threshold, we have followed standard scientific practice and assumed that none exists.

A threshold for the inhaled dose of asbestos in the causation of mesothelioma has not been defined. Indeed, delineation of a threshold may be impossible because of the complexities pertinent to asbestos exposure in humans, which include fiber size and type in addition to dose and the susceptibility of the individual. From inability to delineate a lower threshold, one cannot necessarily conclude that no such threshold exists and that asbestos is oncogenic in humans at any level of exposure, no matter how small. The “one fiber” hypothesis, which holds that even a singe, inhaled asbestos fiber can cause an excess risk of cancer—though not open to conclusive disproof as theory—belongs more to unproven speculation and even hyperbole than to dispassionate science. Ferguson has pointed out that linear dose response models for the lifetime risks of lung cancer and mesothelioma assume no threshold, and they ignore fiber size and type: even if these questionable assumptions are accepted, the resultant deaths are “minuscule” . . .

Craighead and Gibbs state in Asbestos and its Diseases (Oxford University Press, 2008) at pages 107-109:

While it might seem prudent for regulators to assume a linear risk through zero in the absence of proven evidence, it is argued that such an assumption is contrary to what is known about the interaction of asbestos with the respiratory tract. For example, not all fibers in the air are inhaled or penetrate into the lung. It is necessary for fibers to get to the pleura to cause disease, some fibers dissolve and are eliminated and the majority deposit proximally in the respiratory tract. Fibers are coated by biological fluids that may serve to protect the lung. There are DNA repair mechanisms that provide protection in the event genetic damage occurs. Taken together, it is highly improbably that there is a finite risk at close to zero exposure and it seems reasonable to conclude that thresholds exist.

“[T]here is evidence to support the existence of at least a practical threshold for chrysotile that is a level at which risk is undetected (Browne and Gibbs, 1998) . . .”

These observations have considerable practical application, since they imply that any regulatory standard for chrysotile exposure that avoids the development of asbestosis will also protect against mesothelioma and that chrysotile induced mesothelioma is only a historical problem. In fact, the notion of a threshold for chrysotile-induced mesothelioma has been accepted in a recent review of fiber toxicology by the British Health and Safety Executive.

The Doll and Peto (1985) risk assessment for chrysotile-induced lung cancer was based on a linear no-threshold model applied to mortality data from chrysotile textile manufacture. However, the balance of toxicological evidence does not support the no-threshold model for asbestos-induced lung cancer. A practical threshold is likely.

The Report of the Chronic Hazard Advisory Panel on Asbestos to Consumer Product Safety Commission (1983) states at pages 15-16, 28 of 160.:

Dose extrapolation to low levels of exposure is based on a no threshold linear extrapolation. This no threshold assumption is based on: (1) the inability to demonstrate its presence, (2) consistency with accepted theories of cancer induction, and (3) prudence. Linearity of dose response implies that there is neither disproportionately high risk at very low exposures, nor the absence of any risk.

Predictions of risk using responses observed at high exposure levels with varying fiber types to estimate responses to exposure at low levels or with shorter fibers are uncertain. From a public health standpoint, and in the absence of final clarification of the uncertainties, it is prudent to behave as if asbestos fibers may be carcinogenic at low exposure levels and at small particle sizes.

Linearity will be assumed over the entire range of exposure levels for the purposes of estimating risks from occupational studies and for extrapolations to low dose exposure.

Consequently, a linear dose response for mesothelioma is an assumption which has not been verified observationally. (Comments of Kenny Crump)

It appears that linearity would only apply if a single stage cancer model is used. In response to Crump’s comments, Dr. Nicholson stated, “There’s no indication that mesothelioma develops as a result of asbestos fibers acting separately at different stages in the cancer process, which would be required in the multi-stage model to elicit a nonlinear response.

The fact that linearity is tied to a single stage process would argue against its appropriateness if we consider mesothelioma to be a multi-stage process, i.e. the initiator/promoter dichotomy.

59 Fed. Register 40964-40974 at screen 7 of 24 states:

A significant risk finding, however, does not require mathematical precision or anything approaching scientific certainty if the “best available evidence” does not warrant that degree of proof. Rather, the Agency may base its finding largely on policy considerations and has considerable leeway with the kinds of assumptions it applies in interpreting the data supporting it. . . OSHA has always considered that a working lifetime risk of death of over 1 per 1000 from occupational causes is significant. This has been consistently upheld by the courts.

Gaensler states in “Asbestos Exposure in Buildings” (Clinics in Chest Medicine, Vol. 13 No. 2 June 1992) at pages 231-242, 236: “The idea of no-threshold and of unlimited linear extrapolation therefore cannot be accepted without reservation, and the assumption that any exposure will result in some increase of disease is an unproven hypothesis.”

IV. Radiation Papers

It appears that the use of a no–threshold/linear-dose response model to assess risk was first utilized with respect to evaluating cancer risks from ionizing radiation. The use of that model for assessing cancer risk at low doses of ionizing radiation has been criticized on the same bases as its use for evaluation low-dose exposures to chrysotile; the model ignores potent defenses available to repair DNA errors and elimination or preneoplastic cells.

There are potent defenses against the carcinogenic effects of ionizing radiation. Their efficacy is much higher for low doses and dose rates; this is incompatible with the LNT model but is consistent with current models of carcinogenesis. The data suggest that a combination of error-free DNA repair and elimination of preneoplastic cells furnishes practical thresholds.

It is noteworthy that the ATSDR recently presented a range of dose response models in evaluating risk at the El Dorado Hills site in California. That development is discussed in Case et al, “Applying Definitions of “Asbestos” to Environmental and “Low Dose “Exposure Levels and Health Effects, Particularly Malignant Mesothelioma” (Journal of Toxicology and Environmental Health Part B, 14:3-39 (2011), which states at page 25: “In summary, extrapolation from high to low risk, whether based on inferential statistical (e.g., linear no-threshold models, is fraught with uncertainty).”

The 2003 Berman and Crump EPA Technical Support Document demonstrated that available epidemiological studies could not rule out the hypothesis that chrysotile was non-potent for the induction of mesothelioma at any dose. That is a finding inconsistent with the concept of a zero threshold linear dose response model. See Executive Summary Paragraph 6 at page 1.4.

That finding is consistent with conclusions drawn by Yarborough in his paper “Chrysotile as a Cause of Mesothelioma: An Assessment Based on Epidemiology” (Critical Reviews in Toxicology, 36: 165-187 (2008)) which surveyed epidemiological studies involving exposure to chrysotile. Yarborough states, “The scientific and medical information available does not justify the claim that exposure to any amount of any fiber presents an unacceptable health risk.” (Citing Ross and Nolan)